Stereoselective Synthesis of 3-Hydroxy-4-arylcyclopentanones and 4-Arylcyclopentenones through a Heck-Matsuda Desymmetrization of meso cis-4-Cyclopentene-1,3-diol

Article abstract of DOI:10.1002/adsc.201500281

A new palladium-catalyzed route to 3-hydroxy-4-arylcyclopentanones and 4-arylcyclopentenones in a diastereo- and enantioselective manner by a Heck-Matsuda desymmetrization was achieved from the commercially available meso cis-4-cyclopentene-1,3-diol. This method is highly practical, mild, high yielding and is carried out under "open vessel" conditions. Protected and unprotected substrates provide distinct products bearing considerable value as synthetic scaffolds for the synthesis of natural and unnatural bioactive compounds containing a five-membered ring.

Full text of DOI:10.1002/adsc.201500281

COMMUNICATIONS
DOI: 10.1002/adsc.201500281
Stereoselective Synthesis of 3-Hydroxy-4-arylcyclopentanones
and 4-Arylcyclopentenones through a Heck–Matsuda
Desymmetrization of meso cis-4-Cyclopentene-1,3-diol
Rafaela C. Carmonaa and Carlos Roque D. Correiaa,*
a
Instituto de Quıímica, Universidade Estadual de Campinas, Unicamp, Campinas, 13084-971, S¼o Paulo, Brasil
Fax: (+55)-19-3521-3023; phone: (+55)-19-3521-3086; e-mail: roque@iqm.unicamp.br
Received: March 21, 2015; Revised: June 1, 2015; Published online: August 18, 2015
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201500281.
Abstract: A new palladium-catalyzed route to 3-hy-
droxy-4-arylcyclopentanones and 4-arylcyclopente-
nones in a diastereo- and enantioselective manner
by a Heck–Matsuda desymmetrization was achieved
from the commercially available meso cis-4-cyclo-
pentene-1,3-diol. This method is highly practical,
mild, high yielding and is carried out under “open
vessel” conditions. Protected and unprotected sub-
strates provide distinct products bearing considera-
ble value as synthetic scaffolds for the synthesis of
natural and unnatural bioactive compounds con-
taining a five-membered ring.
Figure 1. Biologically active arylcyclopentane compounds.
(Scheme 1).[7] Similar substituted 2-cyclopentanones
were recently reported by Reiserꢀs group.[8]
Keywords: arylcyclopentanones; 4-cyclopentene-
1,3-diol; desymmetrization; enantioselective aryl-
ation; Heck–Matsuda reaction
The Heck–Matsuda reaction is as a powerful tool
for achieving complexity with good atom economy.[9]
In recent years there has been an increase in research
by us and others towards the asymmetric version of
this reaction and its application in organic synthesis.[10]
Herein, we disclose a new and highly efficient Heck–
Matsuda desymmetrization to convert the commer-
Aryl-substituted cyclopentanes and cyclopentanones cially available meso cis-4-cyclopentene-1,3-diol into
constitute ubiquitous scaffolds in many natural and
unnatural products possessing important pharmaco-
logical activity (Figure 1).[1–3] For example, prostaglan-
din AH13205 is an EP2-receptor agonist involved in
the intraocular pressure, whereas indatraline is an an-
tidepressant drug, and beraprost is used in the treat-
ment of prostate cancer.[2,3] Moreover, arylcyclopen-
tenes and arylcyclopentenones play a key role as val-
uable building blocks due to their intrinsic capability
to incorporate diverse nucleophiles and electro-
philes.[4]
Despite their structural simplicity, a concise and
practical synthesis of these scaffolds still remains
a considerable synthetic challenge.[1c,5] Verdaguer
et al. took advantage of an interesting Pauson–Khand
reaction to prepare many arylcyclopentenones,[6
]whereas Helmchen et al. disclosed an efficient multi-
step route to arylcyclopentenones in an enantioselec-
tive fashion to synthesize prostaglandin analogues Scheme 1. Synthesis of 4-arylcyclopentenone scaffolds.
Adv. Synth. Catal. 2015, 357, 2639 – 2643
ꢁ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2639

COMMUNICATIONS
Rafaela C. Carmona and Carlos Roque D. Correia
Table 1. Evaluation of the reaction with QuinOx L1 and
15 min at 408C (entry 3). Because of the effectiveness
of the QuinOx L1 ligand, the catalyst loading was
also evaluated. With only 1 mol% of the Pd catalyst
the reaction provided near quantitative yields of the
Heck product (Table 1, entries 4 and 5). Heck aryla-
tion of meso-diol 1 with the electron-deficient p-chlor-
obenzenediazonium salt (2b) was achieved without
any external ligand in near quantitative yield at 08C
after 4 h (entry 8). In the presence of ligand L1, at
408C, the desired product 3b (Table 1, entry 9, R=
Cl) was obtained in the excellent yield of 97% after
15 min. The Heck product 3b was also obtained in
88% yield using a lower catalyst loading, (5 mol%,
entry 10), whereas a significant decrease in yield was
observed with 1 mol% (44% yield, entry 11). Overall,
the results in Table 1 demonstrated a more efficient
Heck–Matsuda arylation of meso-diol 1 when using
QuinOx ligand L1. The loading amount depended on
the type of aryl substitution.
With these optimized reaction conditions in hand,
we explored the scope of this new Heck–Matsuda re-
action by varying the electronic and substitution pat-
terns of the arenediazonium salts (Scheme 2).
Noticeably, the para- and ortho-methoxy and hy-
droxy-substituted diazonium salts furnished the Heck
products 3a, 3c, 3e and 3f in excellent yields. The first
three products could be obtained in high yields even
with 1 mol% of the catalyst, although for the ortho
phenol cyclopentanone 3f a higher catalyst loading
was required. Additionally, carbamate-substituted
Heck product 3d and the unsubstituted phenyl adduct
3g were obtained in moderate yields.
under “ligandless” conditions.[a]
#
R
T
Lig.
Pd(TFA)2
[mol%]
t
Yield
[%][b]
[oC]
[h]
1
2
3
4
5
6
7
8
p-OMe
p-OMe
p-OMe
p-OMe
p-OMe
p-OMe
p-Cl
p-Cl
p-Cl
p-Cl
p-Cl
40
r.t.
40
40
40
r.t.
r.t.
0
40
40
40
r.t.
0
–
–
10
10
10
5
5
51
70
99
99
99
98
86
98
97
88
44
90
72
on
0.25
1
4
0.75
2
4
0.25
2
3
1
L1
L1
L1
L1
–
1
10
10
10
10
5
1
10
10
–
9
L1
L1
L1
L1
L1
10
11
12
13
p-Cl
p-Cl
on
[a]
Conditions: 1 (0.2 mmol), 2 (0.1 mmol), Pd(TFA)2 (X
mol%), L1 (2X mol%), ZnCO3 (0.05 mmol) in MeOH
(0.10M).
[b]
Determined by 1H NMR. r.t.=room temperature, on=
overnight.
the synthetically useful intermediates trans-3-hydroxy-
Halogenated and trifluoromethylated arenediazoni-
4-arylcyclopentanones or 4-arylcyclopentenones in um salts (2b, 2h–l) provided the desired products 3b,
a racemic and an enantioselective manner. 3h–l, although these reactions required a higher cata-
We began our studies by applying a general proce- lyst loading of 10 mol% for attaining good to excel-
dure previously reported by our group,[11] using lent yields. The exception was the Heck product 3m
Pd(TFA)2 in methanol at 408C. Our initial experi- containing the p-NO2 group, which was obtained in
ments focused on the capability of an N,N-ligand, 4,4- 16% yield, probably due to the instability of the di-
dimethyl-2-(quinolin-2-yl)-4,5-dihydrooxazole
azonium salt in the reaction medium.
(QuinOx, L1) to carry out the Heck arylation in an
As the Heck–Matsuda arylation of cis-4-cyclopen-
efficient way. To evaluate the actual role of the ligand tene-1,3-diol (1) using QuinOx L1 demonstrated good
we also performed the reactions under “ligandless” synthetic potential, we decided to evaluate its asym-
conditions, as shown in Table 1.
metric version employing chiral ligands. Table 2 illus-
As shown in Table 1, the reaction of the meso cis-4- trates our initial results on screening chiral pyridylox-
cyclopentene-1,3-diol (1) with p-methoxybenzenedia- azolines (L2 and L3), bipyridyl-bis-oxazoline (L4), bi-
zonium salt (2a) under ligandless conditions provided soxazoline (L5)[12] and quinoline oxazolines (L6 and
the desired (Æ)-trans-3-hydroxy-4-arylcyclopentanone L7).[13] The choice of N,N-ligands was based on our
(3a) in moderate yields and very high stereoselectivity previous reports concerning the development of the
– only the trans product was observed (entries 1 and enantioselective Heck–Matsuda arylation.[10,11]
2). Arylation was also effective at room temperature,
Most of these ligands slowed down the arylation re-
although it required 12 h for its completion (entry 2). action, except for the quinoline oxazoline ligand (S)-
The Heck arylation was much more efficient when L6, which provided the Heck product in almost quan-
quinoline oxazoline (QuinOx, L1) was employed as titative yield in 15 min (Table 2, entry 4). Overall, the
ligand (Table 1, entries 3–6). Changes in temperature enantioselectivities were only moderate. Aiming at in-
affected basically the reaction time, leading to the creasing the enantioselectivity of the arylation, the in-
corresponding hydroxy ketone 3a quantitatively in fluence of the solvent was evaluated with QuinOx
2640
asc.wiley-vch.de
ꢁ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2015, 357, 2639 – 2643

COMMUNICATIONS
Stereoselective Synthesis of 3-Hydroxy-4-arylcyclopentanones
Table 2. Screening of chiral ligands[a]
#
1
Ligand
Time [h] Yield [%][b] er[c]
5
4
83
73
33:67
36:64
2
3
on
4
61
56
24:76
75:25
4
0.25
2.5
99
99
25:75
25:75
5[d]
6
2
99
71:29
[a]
The absolute stereochemistry shown refers to the major
enantiomer obtained, as indicated in entry 4.
Determined by 1H NMR.
Determined by HPLC.
Performed with 1 mol% of Pd(TFA)2.
[b]
[c]
[d]
ylation was carried out with the QuinOx ligand (S)-
L6 (Scheme 3). As electron-rich arenediazonium salts
performed well in our initial studies, they were tested
first. For comparative purpose, all the reactions were
also carried out in MeOH. Aryl hydroxy ketones 3a,
3c and 3d were obtained in high yields with a moder-
Scheme 2. Scope of the Heck–Matsuda arylation of meso-
diol 1.
ligand L6. After extensive experimentation, it proved ate increase in the enantioselectivity. Contrary to the
beneficial to mix THF with small volumes of MeOH result obtained in Scheme 2, employing QuinOx (S)-
or DMC (dimethyl carbonate), thus combining high L6 under the new conditions, the aryl hydroxy ketone
yields with good enantioselectivities (for a complete 3m, containing the strong electron-withdrawing NO2
list of the solvents evaluated and the respective re- group, was obtained in a good 77% yield in a moder-
sults, see the Supporting Information). The best sol- ate 29:71 er. The subtle influence of the N,N-ligands
vent combinations were THF:MeOH (5%) and was also manifested in MeOH providing 3m in 39%
THF:DMC (1%). The major difference between with an improved er of 18:82 when using PyOx ligand
these two solvent systems is the time for the reaction L3.
to go to completion – 1 h versus 3 h.
To test the importance of the free alcohol function-
A preliminary evaluation of these new reaction ality, we also carried out the Heck–Matsuda reaction
conditions for the enantioselective Heck–Matsuda ar- with the fully protected meso-diol as its corresponding
Adv. Synth. Catal. 2015, 357, 2639 – 2643
ꢁ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
2641

COMMUNICATIONS
Rafaela C. Carmona and Carlos Roque D. Correia
Scheme 5. Enantioselective Heck–Matsuda reaction of the
disilyl ether 4.[a]
nium salts substituted with electron-withdrawing
groups failed to provide the respective arylcyclopen-
tenones.
In conclusion, we have developed an efficient palla-
dium-catalyzed route to 3-hydroxy-4-arylcyclopenta-
nones and 4-arylcyclopentenones in racemic and
enantioselective manner by a Heck–Matsuda reaction.
Our method is highly practical, mild, can be carried
out under “open vessel” conditions, and is basically
a one-step procedure from commercially available
diol 1 and its disilylated derivative 4. The Heck–Mat-
suda products have considerable synthetic value and
can be envisaged as advanced synthetic intermediates
for the synthesis of a diverse range of bioactive com-
pounds.
Scheme 3. The Heck–Matsuda reaction under the new con-
ditions.
Scheme 4. Arylation of meso-4 with ligand (S)-L6.
Experimental Section
General Procedure for Heck–Matsuda
Desymmetrizations
disilyl ether 4. To our surprise, the product obtained
was exclusively the corresponding a,b-unsaturated
ketone 5a in good yield and reasonable enantioselec-
tivity (Scheme 4). Most probably the a,b-unsaturated
ketone 5a was formed through dehydration of the cor-
responding hydroxyl ketone 3. The unsaturated
ketone 5a was previously reported as an advanced in-
A 4-mL sealed vial equipped with a magnetic stir bar was
charged with Pd(TFA)2 (1.0–10.0 mol%), appropiate ligand
(2.0–20.0 mol%) and MeOH (0.93 mL, 0.10M). The flask’s
contents were allowed to stir for 5 min at 408C on a hot
plate to form the precatalyst. Next, the vial was cooled to
room temperature and then ZnCO3 (6.2 mg, 0.05 mmol,
termediate in the synthesis of a range of bioactive 0.5 equiv.), olefin (0.2 mmol, 2.0 equiv.) and the appropriate
arenediazonium salt (2) (0.1 mmol, 1.0 equiv.) were added.
The reaction was carried out at 408C, and accompanied by
a b-naphthol test to verify the diazonium salt’s consumption.
After completion of the reaction, the solvent was removed
under reduced pressure, the crude material was solubilized
with EtOAc, filtered through a short pad of silica gel and
the cake was washed with EtOAc (3”3 mL). After evapora-
tion of the solvent, the yield was measured by 1H NMR
using 1,3-bis(trifluoromethyl)-5-bromobenzene (17.2 mL,
0.1 mmol) as internal standard, and then the crude mixture
compounds and prostaglandin derivatives, thus allow-
ing the unambiguous assignment of the absolute ste-
reochemistry of the Heck products.[6–8,10c,14]
Optimization of this reaction was carried out with
QuinOx ligand (R)-L7 to provide the corresponding
4-arylcyclopentenones 5a, 5c and 5d in moderate to
excellent yields and reasonably good ers (Scheme 5).
So far, arylations of the meso-bis-silyloxycyclopentene
4 are somehow restricted to diazonium salts bearing
electron-donating groups; Heck arylations with diazo- was purified by silica gel flash column chromatography
2642
asc.wiley-vch.de
ꢁ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2015, 357, 2639 – 2643

COMMUNICATIONS
Stereoselective Synthesis of 3-Hydroxy-4-arylcyclopentanones
using the indicated mobile phase to afford the correspond-
ing Heck–Matsuda adducts 3a–m, 5a, 5c and 5d.
2005, 44, 4212–4215; b) M. Marigo, T. C. Wabnitz, D.
Fielenbach, K. A. Jorgensen, Angew. Chem. 2005, 117,
804–807; Angew. Chem. Int. Ed. 2005, 44, 794–797;
c) Y. Hayashi, S. Umemiya, Angew. Chem. 2013, 125,
3534–3536; Angew. Chem. Int. Ed. 2013, 52, 3450–3452;
d) K. C. Nicolaou, P. Heretsch, A. ElMarrouni, C. R. H.
Hale, K. K. Pulukuri, A. K. Kudva, V. Narayan, K. S.
Prabhu, Angew. Chem. Int. Ed. 2014, 53, 10443–10447.
[6] M. RevØs, A. Lledó, Y. Ji, E. Blasi, A. Riera, X. Verda-
guer, Org. Lett. 2012, 14, 3534–3537.
Acknowledgements
We thank the S¼o Paulo Research Foundation FAPESP
grants 2011/23832-6 and 2013/10183-5) and the Brazilian Na-
tional Research Council (CNPq grant 303616/2009-1) for fi-
nancial support and fellowships. We also thank Professor
Gerald B. Hammond, University of Louisville, Kentucky,
USA, for his valuable suggestions during writing of the
manuscript.
[7] a) M. Schelwies, P. Dübon, G. Helmchen, Angew.
Chem. 2006, 118, 2526–2529; Angew. Chem. Int. Ed.
2006, 45, 2466–2469; b) P. Dübon, M. Schelwies, G.
Helmchen, Chem. Eur. J. 2008, 14, 6722–6733.
[8] N. Arisetti, O. Reiser, Org. Lett. 2015, 17, 94–97.
[9] a) E. J. Corey, N. M. Weinshenker, T. K. Schaaf, W.
Huber, J. Am. Chem. Soc. 1969, 91, 5675–5677; b) E. J.
Corey, X. M Cheng, The Logic of Chemical Synthesis
Wiley, New York, 1995; c) P. A. Wender, V. A. Verma,
T. J. Paxton, T. H. Pillow, Acc. Chem. Res. 2008, 41, 40–
49; d) B. M. Trost, Science 1991, 254, 1471–1477.
[10] a) C. R. D. Correia, C. C. Oliveira, A. G. Salles Jr,
E. A. F. Santos, Tetrahedron Lett. 2012, 53, 3325–3328;
b) E. W. Werner, T.-S. Mei, A. J. Burckle, M. S. Sigman,
Science 2012, 338, 1455–1458; c) R. A. Angnes, J. M.
Oliveira, C. C. Oliveira, N. C. Martins, C. R. D. Correia,
Chem. Eur. J. 2014, 20, 13117–13121.
References
[1] a) H. Ohmiya, H. Yorimitsu, K. Oshima, J. Am. Chem.
Soc. 2006, 128, 1886–1889; b) N. K. Mello, S. S. Negus,
Neuropsychopharmacology 2001, 25, 104–117; c) B.
Heasley, Curr. Org. Chem. 2014, 18, 641–686; d) E. B.
Melian, K. L. Goa, Drugs 2002, 62, 107–133.
[2] a) G. Liu, M. E. Shirley, K. N. Van, R. L. McFarlin, D.
Romo, Nat. Chem. 2013, 5, 1049–1057; b) M. Suzuki,
M. Mori, T. Nika, R. Hirata, K. Furuta, T. Ishikawa, R.
Noyori, J. Am. Chem. Soc. 1997, 119, 2376–2385;
c) J. G. Taylor, C. R. D. Correia, J. Org. Chem. 2011, 76,
857–869; d) J. C. Pastre, C. R. D. Correia, Adv. Synth.
Catal. 2009, 351, 1217–1223.
[11] C. C. Oliveira, R. A. Angnes, C. R. D. Correia, J. Org.
Chem. 2013, 78, 4373–4385.
[12] Ligand (R)-L5 was synthesized following a reported
procedure. See: J.-N. Levy, C. M. Latham, L. Roisin, N.
Kandziora, P. D. Fruscia, A. J. P. White, S. Woodward,
M. J. Fuchter, Org. Biomol. Chem. 2011, 9, 512–515.
[13] Synthesis of ligand (R)-L7 is described in the Support-
ing Information. See also: R. C. Carmona, E. P. Schev-
ciw, J. L. P. Albuquerque, E. P. Wendler, A. A. dos
Santos, Green Process Synth. 2013, 2, 35–42.
[3] a) C. D. Funk, Science 2001, 294, 1871–1875; b) J.
Egger, P. Bretscher, S. Freigang, M. Kopf, E. M. Car-
reira, Angew. Chem. 2013, 125, 5490–5494; Angew.
Chem. Int. Ed. 2013, 52, 5382–5385; c) H. P. Acharya,
Y. Kobayashi, Angew. Chem. 2005, 117, 3547–3550;
Angew. Chem. Int. Ed. 2005, 44, 3481–3484; d) M. E.
Jung, J. A. Berliner, L. Koroniak, B. G. Gugiu, A. D.
Watson, Org. Lett. 2008, 10, 4207–4209.
[14] a) Q. Chen, C. Chen, F. Guo, W. Xia, Chem. Commun.
2013, 49, 6433–6435; b) K. Kurihara, N. Sugishita, K.
Oshita, D. Piao, Y. Yamamoto, N. Miyaura, J. Organo-
met. Chem. 2007, 692, 428–435.
[4] F. Menard, D. Perez, D. S. Roman, T. M. Chapman, M.
Lautens, J. Org. Chem. 2010, 75, 4056–4068.
[5] a) Y. Hayashi, H. Gotoh, Y. Hayashi, M. Shoji, Angew.
Chem. 2005, 117, 4284–4287; Angew. Chem. Int. Ed.
Adv. Synth. Catal. 2015, 357, 2639 – 2643
ꢁ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
2643